Atypical Antipsychotic Drug Clinical TrialsResearch Paper

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Treatment Effects: Abilify for Psychosis

The release of aripiprazole to the U.S. market was approved for the treatment of schizophrenia roughly a decade ago. Aripiprazole is a second-generation antipsychotic (SGA) and is described in psychopharmacological literature as a "partial dopaminergic agonist" that also exhibits "partial agonism at serotonin" (Del, 2004). Indeed, over the years since the approval of the drug by the United States Food and Drug Administration in November of 2002, appreciation, the capability of the drug to bind to receptors has been more completely understood, such that, "Aripiprazole can also be classified as a medication with significant 5HT2A-antagonism, and with still other binding characteristics which may be clinically important in individual patients" (Citrome, 2006). Essentially, the term agonism refers to the capacity of a substance to bring about the same physiological effects as some other substance, but it doesn't bind to the same receptor (Del, 2004).

While some studies have comprehensively reviewed the extant literature on aripiprazole for adverse effects, clinical efficacy, the mechanism of action, and pharmacokinetics, this review is concerned only with balancing the adverse effects with clinical efficacy. That is to say, this discussion emphasizes the conventional conundrum a clinician faces with each prescription written: will the patient derive sufficient benefit from the drug to warrant being exposed to the risks of administration of the drug. This question is timely since a decade of use offers practitioners evidence of the efficacy of aripiprazole with various populations, and also provides a corpus of information about the risks of the drug. This discussion proposes that aripiprazole may be a preferred atypical antipsychotic, posing comparable risk for akathisia and a small increased risk of death when compared to placebos (Schneider, 2005).

Akathisia is considered to be a common extrapyramidal side effect of neuroleptic drugs and first-generation antipsychotics, such as haloperidol and thioridazine (Schneider, 2005). Akathisia is described as anxiety that is created just at the thought of having to sit down -- to stay sitting down; it may be manifested muscular quivering (Schneider, 2005). The newer second-generation drugs such as aripiprazole, olanzapine, risperidone, and quetiapine have largely taken market share from the older conventional anti-psychotics because the new drugs are presumed to be safer (Schneider, 2005). In April 2014, Otsuka released a new version of aripiprazole in an extended-release injectable suspension (Abilify Maintena) ("Otsuka," 2014). The new form of aripiprazole was been shown to be associated with higher risk of death than placebos in a 12-week study in which hospitalized schizophrenics, who were experiencing sudden worsening of their symptoms, were administered Abilify Maintena (aripiprazole) ("Otsuka," 2014). The most frequently experienced adverse side effects of the study participants were akathisis, headache, and weight gain ("Otsuka," 2014). Notably, antipsychotic drugs -- particularly atypical antipsychotic drugs -- have been associated to an increased risk of increased mortality in elderly patients with psychosis that is related to their dementia and this risk was found to be sufficiently high to warrant a safety warnings on the drug ("Otsuka," 2014). Indeed, the increased risk of death was estimated to be 1.6 to 1.7 times as great for elderly patients administered atypical antipsychotic drugs than for those patients who received placebos ("Otsuka," 2014). In the populations of 17 trials in which there were placebo-controlled trials, with studies averaging 10 weeks in duration, the death rates were 4.5% versus 2.6% for patients taking atypical antipsychotic drugs vs. those patients who were administered placebos ("Otsuka," 2014).

Incidence of akathisis in patients. Kane, et al. (2010) studied the rates of akathisis in patients as it was related to the type of personality disorder they evidenced. Patients with bipolar I disorder, schizophrenia, and schizophrenia disorder were administered aripiprazole, haloperidol, olanzapine, or a placebo in various studies reviewed by Kane, et al. (2010). The collective safety data from a number of clinical trials in patients with schizophrenia, schizophrenia disorder, and bipolar I disorder were subjected to post hoc analysis (Kane, et al., 2010). The specific data that the researchers reviewed included: 1) the incidence, duration, severity, and time to onset of akathisia; 2) discontinuation of drug due to akathisis; 3) the concomitant use of anticholinergics and/or benzodiazepines; 4) the scores of patients on the Barnes Akathisia Ratings Scale; and 5) the correlation between akathisia and the efficacy of the antipsychotic drugs (Kane, et al., 2010). In the comparison between each of the other drugs and the placebo with aripiprazole, the rate of akathisia was most often higher for aripiprazole (Kane, et al., 2010). The data was as follows:

For patients with schizophrenia and schizophrenic disorder:

Aripiprazole at 9% versus placebos at 6%

Aripiprazole at 12.5% versus haloperidol at 24%

Aripiprazole at 11% versus olanzapine at 6%

For patients with bi-polar disorder:

Aripiprazole at 18% versus placebos at 5% (Kane, et al., 2010).

The clinical manifestations of akathisia were mild-to-moderate in severity, and were the same for each data set: no notable differences were found with respect to the type of disorder or disease (Kane, et al., 2010). In addition, akathisia that emerged during the treatments was not related to poorer clinical outcomes. The rates of discontinuation of medication due to akathisia were low in the trials for schizophrenia, schizophrenic disorder, and bipolar I disorder. The results of the trials for patients with schizophrenia and schizophrenic disorder were as follows:

Aripiprazole at 1.2% and placebo at 0%

Aripiprazole at 0.9% and haloperidol at 2.3%

Aripiprazole at 1.2% and olanzapine at 0.2%

The results of the trials for patients with bipolar disorder were as follows:

Aripiprazole at 2.3% and placebo at 0% (Kane, et al., 2010)

The results of the Kane, et al. (2010) post hoc meta-analysis indicate that when patients with schizophrenia, schizophrenic disorder, and bipolar I disorder who are administered aripiprazole and develop akathisia are unlikely to experience compromised therapeutic efficacy, but are likely to se akathisia emerge early in the treatment, be of mild-to-moderate severity, and seldom lead to discontinuation of Aripiprazole (Kane, et al., 2010).

Reviews of the literature on comparisons between aripiprazole and haloperidol, perphenazine, risperidone, and olanzapine, superior patient tolerance has been found for aripiprazole (Citrome, 2006). At the time of this review, few comparative studies had been conducted for treatments for schizophrenia -- and none were available for bipolar disorder (Citrome, 2006). Reports of the efficacy of Aripiprazole indicate that the drug is superior to placebos and haloperidol over the long-term. But aripiprazole is similar in efficacy to perphenazine and risperidone, but inferior in efficacy to olanzapine (Citrome, 2006).

Mintzer, et al. (2007) conducted a double-blind, multicenter study in which 487 patients with Alzheimer dementia with psychosis were randomly assigned to either aripiprazole or a placebo. The doses tested were 2, 5, or 10 mg per day, and the primary measure of the efficacy of the aripiprazole was the measure of the average change on the Neuropsychiatric Inventory (Mintzer, et al., 2007). Nursing Home (NPI-NH) version measures were from the baseline levels to those on week 10. Psychosis Subscale score Secondary measures included the following: "NPI-NH Total, Clinical Global Impression-Severity of Illness (CGI-S), Brief Psychiatric Rating Scale (BPRS) Core and Total, and the Cohen-Mansfield Agitation Inventory (CMAI) scores" (Mintzer, et al., 2007). The study outcomes showed that aripiprazole was most effective at 10 mg/day, showing greater improvements, at 5 mg/day, aripiprazole produced significant improvements over placebos (Mintzer, et al., 2007). However, aripiprazole was not shown to be effective at 2 mg/day (Mintzer, et al., 2007). The patients with psychosis related to Alzheimer dementia manifested fewer psychotic symptoms, less agitation, and improved clinical global impression when they received 10 mg/day of aripiprazole in the random clinical trials (Mintzer, et al., 2007).

Clinical trials were conducted with Abilify Maintena (aripiprazole), which is the first extended release injectable suspension drug to be approved in the United States for the treatment of schizophrenia ("Otsuka," 2014). This version of the drug aripiprazole can be administered monthly -- given an overlapped dosing of 14 days of an oral antipsychotic -- and has been shown to be an effective approach for uninterrupted coverage in the management of schizophrenia ("Otsuka," 2014). Abilify Maintena effectively reduced relapse risk and the re-emergence of symptoms that are worsening ("Otsuka," 2014). In studies that were "placebo-controlled, randomized withdrawal maintenance trials" with schizophrenic patients, the efficacy of Abilify Maintena was demonstrated ("Otsuka," 2014). Categorically, Abilify Maintena applied for approval with the FDA via a supplemental New Drug Application (sNDA) ("Otsuka," 2014). The sNDA process required efficacy studies, with strong positive results for the drug ("Otsuka," 2014). Measures of the efficacy were shown to be on the primary endpoint for a total score of the Positive and Negative Syndrome Scale (PANSS) at p<.0001 ("Otsuka," 2014). Moreover, Abilify Maintena demonstrated effectiveness on the key secondary endpoint of Clinical Global Impressions Severity (CGI-S) score at p<.0001 ("Otsuka," 2014).

Search strategies. Generalized searches on Google were conducted using the following terms: Aripiprazole, effects of treatment, and psychosis. Scholarly articles were located online for a number of juried periodicals, including international periodicals, PubMed, and MEDLINE. No limitations for year of publication were imposed… [END OF PREVIEW]

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